Immunotherapy design

Novel approaches and designs of biologicals used for cancer immunotherapy as well as changes in the timing, combination sequence, adjuvant choice or route of immunization in immunotherapy regimens; biomarkers of response to therapy

Speck et al. created an oncolytic measles virus encoding CD20- or CEA-targeted bispecific T cell engagers (MV-BiTEs) and demonstrated that intratumoral administration of MV-BiTEs increased T cell infiltration into the tumor, improved survival, and led to durable remissions without signs of toxicity in immunocompetent mice with B16 melanoma, as well as in immunocompromised mice with xenografts of human colorectal carcinoma. T cell infiltration, CD8/FoxP3 mRNA ratio, chemokine mRNA, and markers of exhaustion were all increased.

Speck et al. created an oncolytic measles virus encoding CD20- or CEA-targeted bispecific T cell engagers (MV-BiTEs) and demonstrated that intratumoral administration of MV-BiTEs increased T cell infiltration into the tumor, improved survival, and led to durable remissions without signs of toxicity in immunocompetent mice with B16 melanoma, as well as in immunocompromised mice with xenografts of human colorectal carcinoma. T cell infiltration, CD8/FoxP3 mRNA ratio, chemokine mRNA, and markers of exhaustion were all increased.

PURPOSE: Immunotherapy with bispecific T cell engagers has achieved striking success against hematological malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination. EXPERIMENTAL DESIGN: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers. RESULTS: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T cell infiltration and induction of protective anti-tumor immunity. Additionally, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of PBMCs. CONCLUSION: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs.